Reversal of Hyperglycemia by Insulin-Secreting Rat Bone Marrow- and Blastocyst-Derived Hypoblast Stem Cell-Like Cells

Abstract

β-cell replacement may efficiently cure type 1 diabetic (T1D) patients whose insulin-secreting β-cells have been selectively destroyed by autoantigen-reactive T cells. To generate insulin-secreting cells we used two cell sources: rat multipotent adult progenitor cells (rMAPC) and the highly similar rat extra-embryonic endoderm precursor (rXEN-P) cells isolated under rMAPC conditions from blastocysts (rHypoSC). rMAPC/rHypoSC were sequentially committed to definitive endoderm, pancreatic endoderm, and β-cell like cells. On day 21, 20% of rMAPC/rHypoSC progeny expressed Pdx1 and C-peptide. rMAPCr/HypoSC progeny secreted C-peptide under the stimulus of insulin agonist carbachol, and was inhibited by the L-type voltage-dependent calcium channel blocker nifedipine. When rMAPC or rHypoSC differentiated d21 progeny were grafted under the kidney capsule of streptozotocin-induced diabetic nude mice, hyperglycemia reversed after 4 weeks in 6/10 rMAPC- and 5/10 rHypoSC-transplanted mice. Hyperglycemia recurred within 24 hours of graft removal and the histological analysis of the retrieved grafts revealed presence of Pdx1-, Nkx6.1- and C-peptide-positive cells. The ability of both rMAPC and HypoSC to differentiate to functional β-cell like cells may serve to gain insight into signals that govern β-cell differentiation and aid in developing culture systems to commit other (pluripotent) stem cells to clinically useful β-cells for cell therapy of T1D.

Contribution of different bone marrow-derived cell types in endometrial regeneration using an irradiated murine model

“…Our studies would suggest that EPCs and mOct4 þ BM-HypoSCs contribute mainly to formation of epithelial cells, whereas freshly isolated MSCs cells could be found in the stromal and endothelial compartments. The EPCs can differentiate to endothelium (43) and can also differentiate to epithelial cells such as hepatocytes (15,44) and insulin-producing beta cells (45). In 2002 Reyes et al (14) purified and cultured MAPCs from human, rat and mouse, that expressed Oct-4 and were able to differentiate into multiple cell lineages including endothelial cells and neurons.…”

Disallowed and Allowed Gene Expression: Two Faces of Mature Islet Beta Cells

“…Xenotransplantation studies in which human iPSC-derived beta cells were transplanted under the kidney capsule of mice indicate that such material can improve acute and subacute control of blood glucose. Besides pluripotent stem cells, multipotent adult progenitor cells may also hold potential for reprogramming to beta cells (68). However, safety concerns must be considered.…”

Reprogramming mouse embryo fibroblasts to functional islets without genetic manipulation

“…Immunofluorescence of ICAs for C‐peptide, glucagon, and somatostatin confirmed the existence of functional insulin secretion machinery. C‐peptide, a by‐product of insulin determines the amount of insulin being produced in the body (Kumar et al, ) and is one of the confirmatory tests for functional assessment of ICAs generated from any source of MSC. The glucose stimulated insulin secretion and total insulin content at P4 and P12 finally confirmed their functional activity.…”